The neurotransmitter serotonin is thought to have broad functions in the central nervous system, contributing to the biological basis underlying both behavior and cognition. This neurotransmitter has also been implicated in mental disorders, especially anxiety and depression, and several pharmacological agents used to treat these diseases target serotonergic systems in the brain. Serotonin acts through multiple serotonin receptors to regulate neuronal activity and work during the last decade has made extraordinary advances in our understanding of the basic biology of these receptors. However our understanding of how these receptors function within neurons, what they signal and how they signal in the central nervous system, is still poorly understood. This is an important lacunae, since the biological basis of mental disorders, as well as the development of better treatments, will be grounded in the specific mechanisms used by these receptors. The long term goal of the PI's research program is to help develop a mechanistic understanding, at the molecular level, of serotonin receptor function in central nervous system neurons. Specifically in this application we propose to use a synergistic combination of electrophysiological and molecular biological approaches to understand the signaling mechanisms used by 5-HT2A receptors in the cerebral cortex. The application proposes three Specific Aims. The first of these will elucidate the proximal signaling mechanism used by 5-HT2A receptors to regulate membrane excitability in pyramidal cells of the prefrontal cortex. The second Aim will test the idea that 5-HT2A receptors inhibit the slow calcium-activated potassium current present in pyramidal cells by reducing the concentration of membrane PtdIns(4,5)2. The third Specific Aim will determine how 5-HT2A receptors depolarize and excite pyramidal cells. The results of this project should contribute to our understanding of serotonergic mechanisms in the brain and, as such, contribute to our understanding of mental disorders while supporting the search for more effective treatments. The Public Health Relevance: The neurotransmitter serotonin has been implicated in the genesis of anxiety and depression and in the mechanism of action of several drugs effective in the treatment of mental disorders. The research proposed in this application seeks to elucidate the molecular mechanisms used by serotonin to regulate the function of brain cells and brain circuits. The results of this project should help us better understand mental disorders and contribute to the search of more effective treatments.